Natural history of propionic acidemia in the Amish population

Sarah Ehrenberg; Catherine Walsh Vockley; Paige Heiman; Zineb Ammous; Olivia Wenger; Jerry Vockley; Lina Ghaloul-Gonzalez

doi:10.1016/j.ymgmr.2022.100936

Natural history of propionic acidemia in the Amish population

Mol Genet Metab Rep. 2022 Nov 5:33:100936. doi: 10.1016/j.ymgmr.2022.100936. eCollection 2022 Dec.

Authors

Sarah Ehrenberg^{1

2}, Catherine Walsh Vockley^{2

3}, Paige Heiman², Zineb Ammous⁴, Olivia Wenger^{5

6}, Jerry Vockley^{2

3}, Lina Ghaloul-Gonzalez^{2

3}

Affiliations

¹ University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA.
² Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, PA, USA.
³ Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, PA, USA.
⁴ The Community Health Clinic, Topeka, IN, USA.
⁵ New Leaf Center, Mount Eaton, OH, USA.
⁶ Department of Pediatrics, Akron Children's Hospital, 214 West Bowery Street, Akron, OH 44308, USA.

Abstract

Propionic acidemia (PA) in the Amish is caused by a homozygous pathogenic variant (c.1606A>G; p.Asn536Asp) in the PCCB gene. Amish patients can have borderline or normal newborn screening (NBS) results and symptoms can present at any time from early childhood to mid-adulthood. Early diagnosis and initiation of treatment for PA in the non-Amish population improves patient outcomes. Here, we present data from a retrospective chart review of Amish patients diagnosed with PA from three different medical centers in order to document its natural history in the Amish and determine the influence of treatment on outcomes in this population. A total of 38 patients with average current age 19.9 years (range 4y-45y), 57.9% males, were enrolled in the study. Fourteen patients (36.8%) were diagnosed with a positive newborn screening (NBS) while 24 patients (63.2%) had negative or inconclusive NBS or had no record of NBS in their charts. These 24 patients were diagnosed by screening after a family member was diagnosed with PA (14; 58.3%), following a hospitalization for metabolic acidosis (5; 20.8%), hospitalization for seizures (3; 12.5%) or via cord blood (2; 8.3%). The majority of patients were prescribed a protein restricted diet (32; 84.2%), including metabolic formula (29; 76.3%). Most were treated with carnitine (35; 92.1%), biotin (2; 76.3%) and/or Coenzyme Q10 (16; 42.1%). However, treatment adherence varied widely among patients, with 7 (24.1%) of the patients prescribed metabolic formula reportedly nonadherent. Cardiomyopathy was the most prevalent finding (22; 63.2%), followed by developmental delay/intellectual disability (15; 39.5%), long QT (14; 36.8%), seizures (12; 31.6%), failure to thrive (4; 10.5%), and basal ganglia strokes (3; 7.9%). No difference in outcome was obvious for those diagnosed by NBS and treated early with dietary and supplement management, especially for cardiomyopathy. However, this is a limited retrospective observational study. A prospective study with strict documentation of treatment adherence and universal screening for cardiomyopathy and long QT should be conducted to better study the impact of early detection and treatment. Additional treatment options such as liver transplantation and future therapies such as mRNA or gene therapy should be explored in this population.

Keywords: Amish; Cardiomyopathy; Newborn screen; Propionic Acidemia; Seizures; Treatment.

Grants and funding

K08 HG010490/HG/NHGRI NIH HHS/United States